Chemotherapeutic drugs chronically administered to tumor-bearing mice, using a frequent schedule at doses substantially lower than the maximum tolerated dose (MTD) (i.e., metronomic dosing), can cause sustained and potent antiangiogenic effects by targeting the endothelial cells of newly growing tumor blood vessels. These effects appear to occur in the absence of an increase in the severity of side effects caused by destruction of other cell types normally sensitive to MTD chemotherapy, suggesting a marked and selective sensitivity of activated endothelial cells, the basis of which is unknown. Here we report that protracted exposure of endothelial cells in vitro to low concentrations of several different anticancer agents, including microtubule inhibitors and an alkylating agent, caused marked induction of gene and protein expression of TSP-1, a potent and endothelial-specific inhibitor of angiogenesis. Increases in circulating TSP-1 were also detected in the plasma of human tumor-bearing severe combined immunodeficient mice treated with metronomic low-dose cyclophosphamide. Most importantly, the antiangiogenic and antitumor effects of low-dose continuous cyclophosphamide were lost in TSP-1-null C57BL͞6 mice, whereas, in contrast, these effects were retained by using a MTD schedule of the same drug. Taken together, the results implicate TSP-1 as a secondary mediator of the antiangiogenic effects of at least some low-dose metronomic chemotherapy regimens.endothelial cells ͉ tumor angiogenesis ͉ endogenous inhibitors ͉ TSP-1-null mice
Necrotising fasciitis involving the periorbita is a devastating infection. Potential outcomes range from severe disfigurement, loss of the eye and even to death. Early recognition is critical, although its initially non-distinctive appearance frequently delays diagnosis and treatment. Herein, the authors have performed a systematic review of previously published cases including clinical features, diagnoses and differential diagnoses, pathological characteristics and management. Periorbital necrotising fasciitis is seen mainly in adults with a female predominance (54%); about one-half (47%) of the patients were previously healthy. The infection can follow local blunt trauma (17%), penetrating injuries (22%) and face surgery (11%), but in about one-third of cases (28%) no cause was identified. Non-specific erythema and localised painful swelling of the eyelids characterise the earliest manifestation of the disease, followed by formation of blisters and necrosis of the periorbital skin and subcutaneous tissues. The causative organism in periorbital infection was mainly β-haemolytic Streptococcus alone (50%), occasionally in combination with Staphylococcus aureus (18%). The overall mortality rate was 14.42%. The main risk factor for mortality was the type of causative organism, since all reported cases of death were caused by β-haemolytic Streptococcus alone or associated with other organisms. Unlike necrotising fasciitis affecting other body sites, there was not a strong correlation with age >50 years or the presence of associated chronic illness. Management of periorbital necrotising fasciitis is then based on early distinction of symptoms and signs and aggressive multidisciplinary treatment. Thus, the delay between initial debridement and initiating parenteral broad-spectrum antibiotic therapy should be considered the most critical factor influencing morbidity and mortality.
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